T-cell proliferation and function depends on signals from the antigen-receptor complex (TCR/CD3) and by various co-stimulatory receptors such as CD28 and CTLA-4. The balance of positive and negative signals determines the outcome of the T-cell response of foreign and self-antigen. The most well studied co-stimulatory pairs are CD28/CTLA-4-CD80/CD86. CD28 is constitutively expressed on native and activated CD4 and CD8 positive T cells. CTLA-4 is expressed on activated T cells and plays a negative regulatory role in T cell response. CD80 and CD86 are induced on antigen presenting cells (APC) with their activation (Riha et al., 2010, Self Nonself. 1, 231-240; Sansom et al., 2000, Immunology, 101, 169-177). The discovery of co-stimulatory molecules introduced the possibility of therapeutic intervention at the level of the costimulatory signal without interference with an antigen-receptor (TCR/CD3) signal. One could dampen the co-receptor signal without needing to know the exact nature of the antigen involved in the antigen-receptor complex of T-cell activation cascade (Riha et al., 2010, Self Nonself. 1, 231-240). Therefore co-stimulation blockade has been broadly used to modulate the immune response for organ transplantation, autoimmune diseases as well as cancer treatment (Bour-Jordan et al., 2011, Immunol Rev. 241, 180-205). The higher affinity of CTLA-4 for CD80/CD86 has allowed the use of a CTLA-4-Ig fusion protein to out-compete CD28-CD80/CD86 binding in the treatment of autoimmune disorders (Riha et al., 2010, Self Nonself. 1, 231-240). It was also reported that the suppressive function of natural regulatory T cells is dependent on CTLA-4 (Sansom et al., 2000, Immunology, 101, 169-177; Wing et al., 2008, Science, 322, 271-275).